[A-type lamins and progeroïd syndromes : persistent farnesylation with dramatic effects].
Hutchinson-Gilford Progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and Restrictive Dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary << Laminopathies >>. These heterogeneous disorders are caused by altered Lamin maturation pathway. In physiological conditions, mature Lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, Prelamin A. The major pathophysiological mechanism involved in Progeria is an aberrant splicing due to a de novo heterozygous point mutation, leading to the accumulation of truncated Lamin A precursor. The same aberrant splicing mechanism was involved in RD, whereas the majority of RD cases are caused by ZMPSTE24/FACE1 inactivation, a key enzyme involved in the Lamin A maturation pathway. In functional terms, all these conditions share the same pathophysiological mechanism, i.e. the intranuclear accumulation of Lamin A precursors, which cannot be fully processed and exert a toxic effect on nuclear homeostasis. In this article, we review the structure and functions of A-type Lamins, focusing namely on HGPS, RD or MAD disorders, in relation to existing animal models and possible future therapeutic approaches.
Navarro
Claire L
CL
Université de la Méditerranée, Inserm UMR 910, Génétique Médicale et Génomique Fonctionnelle, Faculté de médecine de Marseille 27, boulevard Jean Moulin, 13005 Marseille, France.
Poitelon
Yannick
Y
Lévy
Nicolas
N
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D004195:Disease Models, Animal; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D054876:Prenylation; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome
C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; C090764:prelamin A; D002784:Cholesterol; D051231:Farnesyltranstransferase; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse